Necrotizing Enterocolitis: Intraluminal Biochemistry in Human Neonates and a Rabbit Model

Abstract Background Claudin proteins are a component of tight junctions found in cell-cell adhesion complexes. A central feature of necrotizing enterocolitis (NEC) is intestinal permeability, with changes to claudin proteins potentially contributing to intestinal instability, inflammation, and the progression of NEC. A current area of interest is the development of a novel, noninvasive biomarker for the detection of NEC in neonates at risk of developing this disease, in order to reduce morbidity and mortality through earlier intervention. Aims This review aims to explore the relevance of claudin proteins in the pathophysiology of NEC and their potential usefulness as a biomarker. Methods This review was conducted using the search terms “claudin” + “necrotizing enterocolitis”, with 27 papers selected for review. Results Claudin proteins appear to have a role in the stability of the gut epithelium through the regulation of intestinal permeability, maturity, and inflammation. Formula feeding has been shown to promote inflammation and result in changes to claudin proteins, while breastfeeding and certain nutritional supplements lead to reduced inflammation and improved intestinal stability as demonstrated through changes to claudin protein expression. Preliminary studies in human neonates suggest that urinary claudin measurements may be used to predict the development of NEC. Conclusions Alterations to claudin proteins may reflect changes seen to intestinal permeability and inflammation in the context of NEC. Further research is necessary to understand the relevance of claudin proteins in the pathophysiology of NEC and their use as a biomarker.

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Anidulafungin for Neonatal Hematogenous Candida Meningoencephalitis: Identification of Candidate Regimens for Humans Using a Translational Pharmacological Approach

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05826-11 ◽

2011 ◽

Vol 56 (2) ◽

pp. 708-714 ◽

Cited By ~ 25

Author(s):

Peter A. Warn ◽

Joanne Livermore ◽

Susan Howard ◽

Timothy W. Felton ◽

Andrew Sharp ◽

...

Keyword(s):

Clinical Care ◽

Rabbit Model ◽

Data Set ◽

Antifungal Effect ◽

Content Type ◽

Serious Infection ◽

Population Pk ◽

Dose Dependent ◽

Human Neonates ◽

Bridging Studies

ABSTRACTHematogenousCandidameningoencephalitis (HCME) is a serious infection in premature neonates. Anidulafungin is an echinocandin antifungal agent with potent activity againstCandidaspp., but its efficacy and optimal regimens for human neonates with HCME are not known. A well-validated rabbit model of HCME was used to define pharmacokinetic-pharmacodynamic (PK-PD) relationships of anidulafungin. A mathematical model was fitted to the entire data set. The experimental data were bridged to humans. A population PK model was fitted to the data from human neonates receiving anidulafungin receiving a loading dose of 3 mg/kg, followed by 1.5 mg/kg/day. Monte Carlo simulations were performed to identify candidate anidulafungin regimens for humans. All untreated rabbits succumbed by ≤96 h postinoculation. The PK of anidulafungin was linear with dose-dependent penetration into the cerebrum. Anidulafungin exerted a rapid antifungal effect that was apparent in the first dosing interval. Near-maximal antifungal activity was observed with dosages of 10 to 20 mg/kg/day. The bridging studies suggested that the current regimen of first 3 mg/kg, followed by 1.5 mg/kg/day, is suboptimal. Higher dosages were associated with progressively greater antifungal effect. Anidulafungin is effective for the treatment of experimental HCME. Higher dosages than those currently used for clinical care are required for maximal antifungal effect.

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SOD prevents damage and attenuates eicosanoid release in a rabbit model of necrotizing enterocolitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1988.255.5.g556 ◽

1988 ◽

Vol 255 (5) ◽

pp. G556-G565 ◽

Cited By ~ 4

Author(s):

M. J. Miller ◽

H. McNeill ◽

K. M. Mullane ◽

S. J. Caravella ◽

D. A. Clark

Keyword(s):

Necrotizing Enterocolitis ◽

Ex Vivo ◽

Rabbit Model ◽

Platelet Activating Factor ◽

Leukotriene B4 ◽

Intestinal Damage ◽

Vascular Effects ◽

Fluid Shifts ◽

Eicosanoid Release ◽

Local Generation

Necrotizing enterocolitis (NEC) was produced in anesthetized rabbits by transmural injection of intestinal loops with an acidified solution of casein and calcium gluconate, mimicking the luminal milieu of afflicted neonates. Intravenous infusion of superoxide dismutase (SOD) 15 min after NEC induction prevented intestinal damage. In ex vivo perfused intestinal loops, we determined the sites of eicosanoid release and their contribution to the vascular effects of N-formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) in damaged and SOD-salvaged intestine. The vascular effluent was the primary site of stimulated eicosanoid release. The vascular responses to fMLP (vasoconstriction) and PAF (vasodilation) were not altered by SOD, although vascular resistance was higher in the SOD group. SOD treatment attenuated 1) transmural fluid shifts in ex vivo perfused intestinal preparations, an index of vascular permeability, 2) fMLP-induced prostaglandin E2, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and leukotriene B4 (LTB4) release, and 3) PAF-induced release of 6-keto-PGF1 alpha and LTB4. Stimulated thromboxane B2 release was not altered by SOD. Thus NEC can be established by a luminal insult that causes local generation of free radicals and exaggerated release of prostaglandins and leukotrienes.

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Doppler Sonographic Findings in an Experimental Rabbit Model of Necrotizing Enterocolitis

Journal of Ultrasound in Medicine ◽

10.7863/jum.2010.29.3.379 ◽

2010 ◽

Vol 29 (3) ◽

pp. 379-386 ◽

Cited By ~ 10

Author(s):

Young-Hun Choi ◽

In-One Kim ◽

Jung-Eun Cheon ◽

Je-Eun Kim ◽

Ee-Kyung Kim ◽

...

Keyword(s):

Necrotizing Enterocolitis ◽

Rabbit Model

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Lung ultrasound features and relationships with respiratory mechanics of evolving BPD in preterm rabbits and human neonates

Journal of Applied Physiology ◽

10.1152/japplphysiol.00300.2021 ◽

2021 ◽

Author(s):

Barbara Loi ◽

Costanza Casiraghi ◽

Chiara Catozzi ◽

Matteo Storti ◽

Monica Lucattelli ◽

...

Keyword(s):

Lung Ultrasound ◽

Rabbit Model ◽

Classical Mechanics ◽

Lung Mechanics ◽

Preterm Neonates ◽

Ultrasound Images ◽

Rabbit Lung ◽

Neonatal Lung ◽

Ultrasound Score ◽

Human Neonates

Evolving broncho-pulmonary dysplasia (BPD) is a regionally heterogeneous disorder characterized by impaired alveolarization leading to lung aeration inhomogeneities. Hyperoxia-exposed preterm rabbits have been proposed to mimic evolving BPD and we aim to verify if this model has the same lung ultrasound and mechanical features of evolving BPD in human neonates. Twenty-five preterm rabbits and twenty-five neonates with evolving BPD were enrolled and subjected to semi-quantitative lung ultrasound and lung mechanics measurement. A modified rabbit lung ultrasound score (rLUS), the previously validated neonatal lung ultrasound score (LUS) and classical mechanics measurements were obtained. Lung ultrasound images were also recorded and evaluated by two independent observers with different expertise blinded to each other's evaluation. Lung ultrasound findings were equally heterogeneous both in rabbits as in human neonates: images were very similar and encompassed all the classical lung ultrasound semiology. The inter-rater absolute agreement for the evaluation of lung ultrasound images in rabbits was very high (ICC: 0.989 (95%CI: 0.975-0.995); p<0.0001) and there was no difference between the two observers. Lung mechanics parameters were similarly altered both in rabbits and human neonates. There were significant correlations between airway resistances and lung ultrasound scores both in rabbits (r=0.519; p=0.008) and in neonates (r=0.409; p=0.042). No significant correlation between rLUS, LUS and any other mechanics parameter. Lung ultrasound was easy to be performed and accurate even in these small animals and with a short training. In conclusion, the preterm rabbit model fairly reproduces the lung ultrasound and mechanical characteristics of preterm neonates with evolving BPD.

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